We have designed 4 different single chain Fv molecules as antigen-recognition domains for anti-CD30 CARs and compared CARs with these different scFvs in vitro. We selected the optimal scFv, and tested it in different CAR designs in vitro and in mouse tumor models. We have identified an optimal scFv and CAR design for further development. This work led to 2 CARs that are both highly effective in mice. We have selected one of these CARs for a phase I clinical trial. Simultaneous work has been completed that has led to generation of a clinical-grade lentiviral vector encoding this CAR. We have completed work on a clinical protocol for a clinical trial of the fully-human anti-CD30 CAR, and this protocol has been approved by the NCI Institutional Review Board. We continue preclinical work to improve anti-CD30 CAR design and T-cell culture methods with an emphasis on comparing different hinge and transmembrane domains as well as comparing CD28 versus 4-1BB costimulatory domains . A clinical trial of T cells expressing an anti-CD30 CAR has opened, and the first 2 treated patients have obtained partial remissions with mild toxicity. We will continue to accrue patients to this dose-escalation phase I clinical trial.